Cells can respond to low oxygen tension, or hypoxia by increasing oxygen delivery or adapting to decreased oxygen availability. An essential regulator of oxygen homeostasis is the transcription factor, hypoxia-inducible factor-1 (HIF-1). HIF-1 exquisitely regulates a variety of processes to respond to hypoxia and is itself exquisitely regulated to prevent an inappropriate hypoxic response. The objective of this proposal is to determine the role of HIF-1 in the development and progression of cancer, ultimately to determine whether HIF-1 and its downstream targets are good candidates for rational drug design or whether they can be used as diagnostic or prognostic markers. Achieving this goal requires a biochemical and cellular understanding of the dynamic relationship between HIF-1 and its negative regulators, the prolyl hydroxylase enzymes. How these prolyl hydroxylases contribute to the regulation of HIF-1 and thus the development or progression of cancer is poorly understood. Genetic systems to knockdown the function of these enzymes will be instrumental in understanding the contribution of these enzymes to tumorigenesis. [unreadable] [unreadable] [unreadable] [unreadable]